1. Field of the Invention
The present invention lies firmly within the fields of drug, bio-effective and body treating compositions, more specifically drugs and methods for acute and chronic pain relief and acute and chronic intervention for drug abuse.
2. Description of the Prior Art
The present invention relates to novel hybrid alkaloid/peptide chimeric molecules for the treatment of pain. The relief of suffering due to pain is an important objective of clinical practice and for restoring quality to life and the ability to function normally to pain sufferers.
Pain represents an integrated, complex, perception of noxious stimuli originating from somatic elements such as arms and legs and/or from visceral organs such as heart and liver. Mechanistically, acute pain signaling involves noxious stimulation of free nerve endings innervating somatic elements and/or visceral organs leading to the activation of different types of slowly-conducting afferent fibers of the A delta and C classes, terminating in the dorsal sensory spinal cord. A significantly more complex etiology underlies the initiation and persistence of chronic pain syndromes. This involves initial damage to peripheral nerves innervating somatic and visceral fields, persistent immunological challenge by cytokines and inflammatory mediators, reorganization of spinal cord and brainstem relay systems, and higher cortical adaptation.
From an established pharmacological perspective, opioids remain the key agents of choice for treatment of a wide variety of acute and chronic pain states. The prototype opioid analgesic or painkiller is morphine. Morphine and morphine-related opioids produce their painkilling effects by profound pharmacological inhibition of neurons of the peripheral/sensory nervous system (PNS) and the central nervous system (CNS). The biochemical and cellular effects of morphine, including profound analgesia, are transduced through a membrane-associated G-protein designated the mu (μ) opioid receptor (MOR), found in high concentrations within the PNS and CNS.
Unfortunately, the high degree of pain relief afforded by morphine and similar opioid compounds is associated with many undesirable side effects, all mediated through activation of the MOR. They include drowsiness, nausea, emesis (vomiting), changes in mood (dysphoria), respiratory depression, decreased gastrointestinal motility (constipation), pruritis (itching), alterations in endocrine and autonomic function, and physical and psychological dependence leading to addiction.
In addition to the adverse physiological sequelae listed above, a major associated risk is that repeated daily administrations of morphine or morphine-like opioids will eventually induce significant tolerance to the therapeutic effects of the drug as well as initiating some degree of physical dependence. Here opioid tolerance is operationally defined as an escalating dosage regimen required to achieve the same magnitude of pain relief over a defined time course.
The administration of escalating dosage so as to achieve the same magnitude of pain relief can increase the likelihood and the severity of undesirable side effects such as drowsiness, nausea, emesis (vomiting), changes in mood (dysphoria), respiratory depression, decreased gastrointestinal motility (constipation), pruritis (itching), alterations in endocrine and autonomic function.
The degree of tolerance and physical dependence will vary with the particular opioid employed, the correlation with MOR-selective opioids such as morphine being high, the frequency of administration, and the quantity of opioid administered.
In a wide variety of clinical indications requiring prolonged use of opioids, tolerance induction and addiction are closely linked, with the development of physical and psychological dependence always a major concern. Addiction with physical dependence can be difficult to treat due to the effects of withdrawal associated with dependence.
From an established clinical perspective, when morphine and/or similar opioid analgesics are administered, the treating health care provider must recognize that only symptomatic treatment of pain is being provided. The health care provider must therefore constantly weigh the benefits of this immediate (day by day) relief against its costs and risks to the patient. Accordingly, a decision to relieve the chronic pain in particular clinical situations via administration of current opioid analgesics may be short sighted and an actual disservice to the patient.
Morphine and related MOR-selective opioids also relieve suffering by ameliorating the emotional or affective component of the painful experience. Consequently, if little or no external emotional support is provided, for example by biofeedback procedures or cognitive behavioral therapy, some patients may require considerably more than the average dose of an opioid to experience any relief from pain; similarly, others may require more frequent administration. These are major factors supporting the use of patient-controlled analgesia (PCA) for acute post-operative pain control, where the affective aspects of painful experience are successfully addressed. In effect, many health care providers frequently tend to prescribe therapeutic dosages of opioids that are either too low and/or administered at infrequent time intervals out of an exaggerated concern for minimizing addiction potential. The resultant therapeutic regimen fails to provide adequate analgesia over time.
In light of the caveats listed above, many health care providers are constantly encouraged to employ measures other than opioid drugs to relieve chronic or acute pain, even when such alternative methods show limited efficacy in the absence of opioid therapy. These typically include the use of local nerve block, combinations of antidepressant and anticonvulsant CNS drugs, electrical stimulation, acupuncture, hypnosis, or behavioral modification (Reuler et al., Ann. Intern. Med. 93:588-596 (1980)). Additionally, many practitioners respond to their patients' continued complaints of inadequate pain relief with even more exaggerated concerns about dependency. This is done despite the high probability that the request for more opioid is only the expected consequence of the inadequate dosage originally prescribed. (Sriwatanakul et al., J.A.M.A. 250:926-929 (1983))
It has also been documented that children are probably more apt to receive inadequate dosages for pain than are adults based on the same type of reasoning concerning tolerance and dependence Schechter. (N. L., Curr. Probl. Pediatr. 15 (1985))
Finally, it is useful to remember that the typical initial dose of morphine (10 mg/70 kg body weight) relieves post-operative pain satisfactorily in only about two-thirds of patients. (See page 511, Gilman et al., The Pharmacological Basis of Therapeutics)
Morphine/opioid-induced physiological and psychological side effects pose major obstacles to their unfettered, widespread usage as the mainspring therapeutic regimen for pain relief across clinical populations in the United State and abroad. Intrinsic issues of opioid safety and efficacy were addressed by a prior invention (U.S. Pat. No. 5,891,842), where I established a therapeutic procedure or treatment regimen for inducing or eliciting a markedly enhanced opioid-dependent analgesic response within a living subject. That treatment methodology employs the concurrent administration of two recognized, self-contradicting and physiologically antagonistic compounds, the opioid analgesic morphine sulfate and the tachykinin peptide substance P(SP), at individual concentrations that had been empirically shown to have either marginal or completely ineffectual pharmacological properties in vivo. Because noxiously challenged or damaged sensory nerves release a variety of excitatory chemical mediators, including SP, the tachykinin SP had been previously designated as a nociceptive or pain-producing peptide transmitter at the spinal level. Nevertheless, my research demonstrates that at prescribed low nanogram concentrations SP appears to be a potent regulator of opioid analgesia in vivo. Despite this apparent contradiction and the previously demonstrated physiological antagonism between these compounds in their traditional formats and conventionally used concentrations, my novel treatment process demonstrated a synergistic relationship period of time, and that an effective and efficacious opioid-induced analgesia results within the living subject from the process.
Unfortunately, because my prior invention requires the concurrent administration of two different self-contradicting and physiologically antagonistic compounds, SP and morphine, it presents difficulties in successfully establishing and testing the appropriate concurrent dosages for efficacious and safe administration in humans, as reflected by FDA and NIH clinical testing guidelines.
While morphine is the prototype opioid analgesic or painkiller, its complex alkaloid characteristics differ greatly from those of peptides, and SP is a peptide. In subsequent research, therefore, collaborators and I combined the active pharmacological domains of SP and the peptide endomorphin-2 into one chemical entity: a novel seven amino acid peptide chimera, designated ESP7. Repeated administration of the chimeric molecule into the rat spinal cord milieu produced analgesia mediated by the MOR without a loss of potency over a 5-day time course. Essentially, ESP7 represented a non-tolerance forming compound with future potential as a specialized spinal analgesic for control of acute and/or chronic pain. (Foran, et al., A Substance P-opioid chimeric peptide as a unique non-tolerance-forming analgesic, 97 Proceedings of the National Academy of Sciences 13 (2000))
Although ESP7 provided the advantage of a single analgesic molecule, it has several unfortunate disadvantages. Operationally, the peptide chemical nature of ESP7 restricts its effective dosage and time-effect relationship within the CNS due to significant metabolism in the blood stream. This is supported by collected pharmacological data indicating significant difficulties encountered by peptide drug candidates for crossing the mammalian blood-brain barrier (BBB) (Egleton R D, Abbruscato T J, Thomas S A, Davis T P Transport of opioid peptides into the central nervous system. J Pharm Sci 1998; 87(11):1433-9), as well as absorption after oral administration. (Borchardt R, Optimizing oral absorption of peptides using prodrug strategies. J Control Release 1999;62(1-2):231-8) Because of this, ESP7 envisioned intrathecal administration and administration through other means could yield short duration or no analgesia. Additionally, the peptide endomorphin-2 does not have the full analgesic effect of morphine.
Morphine is a relatively complex organic molecule, termed an alkaloid due to its positively charged nitrogen group, unlike the endogenous peptide endomorphin-2 which provided the analgesic moiety in ESP7. Morphine is a highly efficacious MOR-selective opioid analgesic and will cross the human BBB, as will its active metabolite morphine 6-glucuronide. (Stain-Texier F, Boschi G, Sandouk P, Scherrmann J M, Elevated concentration of morphine 6-beta-D-glucuronide in brain extracellular fluid despite low blood-brain barrier permeability. Br J Pharmacol 1999; 128(4):917-24)
Substance P, however, is a peptide. Chimeric hybrid molecules possessing an alkaloid moiety and a peptide moiety are unknown to the literature of analgesia and to clinical practice. Chimeric hybrid molecules possessing an alkaloid moiety to activate the human MOR and a peptide moiety to concurrently activate the human SP receptor (SPR) are unknown to the literature of analgesia and to clinical practice. Chimeric hybrid molecules comprised of one moiety with a chemically modified morphine molecule to activate the human MOR and another moiety with a SP fragment to activate the human SPR are unknown to the literature of analgesia and to clinical practice.
Another major challenge is to design a molecule that will cross the BBB and produce analgesia in a living subject, while inhibiting tolerance development and dependence formation. Such a molecule should be structured in such a way as to activate simultaneously the MOR and SPR domains in the PNS and/or CNS. With respect to both morphine and SP, a variety of alkaloid morphine and SP peptide fragments can be synthesized, having potentially different pharmacological effects if bound to another moiety. No obvious method is known for the SP moiety to be cross-linked to a morphine alkaloid moiety in a fashion that the resulting molecule will allow simultaneous activation of both the MOR and SPR receptors. Chimeric hybrid molecules with a moiety comprised of a chemically modified morphine molecule to provide the method to transport active SP fragments across the mammalian blood brain barrier are unknown to the literature of analgesia and to clinical practice.
Presently there also are no analgesic opioid molecules or chimeras that have been developed that achieve effective analgesia for mammalian acute or chronic pain without significant tolerance development and dependence formation.
Objects and Advantages. I have invented novel and useful compositions and methods employing heretofore unknown morphine-SP hybrid chimeras, as I have described below. Several objects and advantages of my present invention are:    a. a molecule that can be dosed to produce effective analgesia in a living subject, i.e., a mammal (an animal class which includes humans), while inhibiting tolerance development;    b. a molecule that can be dosed to produce effective analgesia in a living subject while inhibiting dependence formation;    c. a molecule that can be dosed to produce effective opioid analgesia and that can be administered through a variety of methods of clinical administration, including oral, systemic and intrathecal administration;    d. a molecule that can be dosed to produce effective opioid analgesia without significant restriction on its effective dosage and time-effect relationship within the CNS due to metabolism in the blood stream;    e. a molecule that can be dosed to yield effective opioid analgesia with a reduction in the likelihood of undesirable side effects;    f. a molecule that can be dosed to produce effective opioid analgesia with a reduction in the likely severity of undesirable side effects that become manifested by the patient;    g. an opioid analgesic that can be dosed for administration to children without undue tolerance development;    h. an opioid analgesic that can be dosed for administration to children without undue dependence formation; and    i. an opioid analgesic suitable for PCA in the treatment of chronic and/or acute pain.
Additional objects and advantages of my present invention are:    a. to provide a method for treating pain with opioid analgesia and little or no opioid tolerance development;    b. to provide a method for treating pain with opioid analgesia and little or no opioid dependence formation;    c. to provide a method for treating pain with opioid analgesia with reduced likelihood of undesirable side effects;    d. to provide a method of opioid analgesia for PCA for acute and/or chronic pain; and    e. to provide a method of treating drug abuse by administering as a substitute for the abused drug an analgesic that elicits little or no tolerance development or dependency formation and thereafter adjusting the dosage as tolerance and/or dependence is modulated.
Still further objects and advantages will become apparent from a consideration of the following description of my invention.